Reversible encephalitis-like episodes in fragile X-associated tremor/ataxia syndrome: a case report.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by CGG repeat expansion of FMR1 gene. Both FXTAS and neuronal intranuclear inclusion disease (NIID) belong to polyglycine diseases and present similar clinical, radiological, and pathological features, making it difficult to distinguish these diseases. Reversible encephalitis-like attacks are often observed in NIID. It is unclear whether they are presented in FXTAS and can be used for differential diagnosis of NIID and FXTAS. CASE PRESENTATION: A 63-year-old Chinese male with late-onset gait disturbance, cognitive decline, and reversible attacks of fever, consciousness impairment, dizziness, vomiting, and urinary incontinence underwent neurological assessment and examinations, including laboratory tests, electroencephalogram test, imaging, skin biopsy, and genetic test. Brain MRI showed T2 hyperintensities in middle cerebellar peduncle and cerebrum, in addition to cerebellar atrophy and DWI hyperintensities along the corticomedullary junction. Lesions in the brainstem were observed. Skin biopsy showed p62-positive intranuclear inclusions. The possibilities of hypoglycemia, lactic acidosis, epileptic seizures, and cerebrovascular attacks were excluded. Genetic analysis revealed CGG repeat expansion in FMR1 gene, and the number of repeats was 111. The patient was finally diagnosed as FXTAS. He received supportive treatment as well as symptomatic treatment during hospitalization. His encephalitic symptoms were completely relieved within one week. CONCLUSIONS: This is a detailed report of a case of FXTAS with reversible encephalitis-like episodes. This report provides new information for the possible and rare features of FXTAS, highlighting that encephalitis-like episodes are common in polyglycine diseases and unable to be used for differential diagnosis.

Cardiopulmonary Coupling Spectrogram as an Ambulatory Method for Assessing Sleep Disorders in Patients With Autoimmune Encephalitis.

BACKGROUND AND OBJECTIVES: Sleep disorders are a common and important clinical feature in patients with autoimmune encephalitis (AE); however, they are poorly understood. We aimed to evaluate whether cardiopulmonary coupling (CPC), an electrocardiogram-based portable sleep monitoring technology, can be used to assess sleep disorders in patients with AE. METHODS: Patients fulfilling the diagnostic criteria of AE were age- and sex-matched with recruited healthy control subjects. All patients and subjects received CPC testing between August 2020 and December 2022. Demographic data, clinical information, and Pittsburgh Sleep Quality Index (PSQI) scores were collected from the medical records. Data analysis was performed using R language programming software. RESULTS: There were 60 patients with AE (age 26.0 [19.8-37.5] years, male 55%) and 66 healthy control subjects (age 30.0 [25.8-32.0] years, male 53%) included in this study. Compared with healthy subjects, patients with AE had higher PSQI scores (7.00 [6.00-8.00] vs 3.00 [2.00-4.00], p < 0.001), lower sleep efficiency (SE 80% [71%-87%] vs 92% [84%-95%], p < 0.001), lower percentage of high-frequency coupling (25% [14%-43%] vs 45% [38%-53%], p < 0.001), higher percentage of REM sleep (19% ± 9% vs 15% ± 7%, p < 0.001), higher percentage of wakefulness (W% 16% [11%-25%] vs 8% [5%-16%], p = 0.074), higher low-frequency to high-frequency ratio (LF/HF 1.29 [0.82-2.40] vs 0.91 [0.67-1.29], p = 0.001), and a higher CPC-derived respiratory disturbance index (9.78 [0.50-22.2] vs 2.95 [0.40-6.53], p < 0.001). Follow-up evaluation of 14 patients showed a decrease in the PSQI score (8.00 [6.00-9.00] vs 6.00 [5.00-7.00], p = 0.008), an increased SE (79% [69%-86%] vs 89% [76%-91%], p = 0.030), and a decreased W% (20% [11%-30%] vs 11% [8%-24], p = 0.035). Multiple linear regression indicated that SE (-7.49 [-9.77 to -5.21], p < 0.001) and LF/HF ratio (0.37 [0.13-0.6], p = 0.004) were independent factors affecting PSQI scores in patients with AE. DISCUSSION: Sleep disorders with autonomic dysfunction are common in patients with AE. Improvements in the PSQI score and SE precede the restoration of sleep microstructural disruption in the remission stage. CPC parameters may be useful in predicting sleep disorders in patients with AE.

Reversible dementia and insomnia in ABGA related encephalitis.

BACKGROUND: ABGAs are historically associated with Encephalitis Lethargica (EL). Typically ABGAs are also found in children resulting in a variety of neuropsychiatric and extrapyramidal disorders, rare cases are reported in adults with atypical movement disorders. No description of basal ganglia reversible lesions related to ABGAs are reported and these antibodies are not included in the list of autoimmune encephalitis. METHODS AND RESULTS: A 55 years old female presented sub-acute onset of an anxious-depressive disorder and obsessive-compulsive behavior associated with intractable insomnia affecting sleep onset and sleep maintenance. Brain-MRI showed diffuse hyperintensities on FLAIR sequences in the basal ganglia. A therapy with IV-immunoglobulin was started and the clinical condition improved dramatically and insomnia and psychiatric symptoms resolved completely. CONCLUSION: Our case highlights the importance of making a fast diagnosis. When caught early ABGAs-related encephalitis is susceptible of a good outcome and response to treatment. Reversible insomnia and dementia in our case expand ABGA clinical presentation in adults and favors the hypothesis of an immune pathogenesis for Encephalitis Lethargica, especially in the hyperkinetic form as previously suggested, as in our case.

Fingolimod improves diffuse brain injury by promoting AQP4 polarization and functional recovery of the glymphatic system.

BACKGROUND: Diffuse brain injury (DBI) models are characterized by intense global brain inflammation and edema, which characterize the most severe form of TBI. In a previous experiment, we found that fingolimod promoted recovery after controlled cortical impact injury (CCI) by modulating inflammation around brain lesions. However, it remains unclear whether fingolimod can also attenuate DBI because of its different injury mechanisms. Furthermore, whether fingolimod has additional underlying effects on repairing DBI is unknown. METHODS: The impact acceleration model of DBI was established in adult Sprague-Dawley rats. Fingolimod (0.5 mg/kg) was administered 0.5, 24, and 48 h after injury for 3 consecutive days. Immunohistochemistry, immunofluorescence analysis, cytokine array, and western blotting were used to evaluate inflammatory cells, inflammatory factors, AQP4 polarization, apoptosis in brain cells, and the accumulation of APP after DBI in rats. To evaluate the function of the glymphatic system (GS), a fluorescent tracer was injected into the cistern. The neural function of rats with DBI was evaluated using various tests, including the modified neurological severity score (mNSS), horizontal ladder-crossing test, beam walking test, and tape sensing and removal test. Brain water content was also measured. RESULTS: Fingolimod administration for 3 consecutive days could reduce the levels of inflammatory cytokines, neutrophil recruitment, microglia, and astrocyte activation in the brain following DBI. Moreover, fingolimod reduced apoptotic protein expression, brain cell apoptosis, brain edema, and APP accumulation. Additionally, fingolimod inhibited the loss of AQP4 polarization, improved lymphatic system function, and reduced damage to nervous system function. Notably, inhibiting the GS weakened the therapeutic effect of fingolimod on the neurological function of rats with DBI and increased the accumulation of APP in the brain. CONCLUSIONS: In brief, these findings suggest that fingolimod alleviates whole-brain inflammation and GS system damage after DBI and that inhibiting the GS could weaken the positive effect of fingolimod on nerve function in rats with DBI. Thus, inhibiting inflammation and regulating the GS may be critical for the therapeutic effect of fingolimod on DBI.

Acetazolamide as an effective treatment for pilomotor seizures in autoimmune encephalitis.

Pilomotor seizures are strongly associated with autoimmune encephalitis (AE), particularly anti-LGI1 encephalitis. The carbonic anhydrase inhibitor acetazolamide may have special efficacy for treating AE-associated pilomotor seizures. Six patients with AE (five anti-LGI1, one seronegative) and temporal lobe pilomotor seizures (five with seizures inducible by hyperventilation) were treated with acetazolamide, administered in a cycling (2-days-ON, 4-days-OFF) regimen to offset tolerance. Seizures were assessed during epilepsy monitoring unit (EMU) recordings in four inpatients (one of whom also maintained an outpatient seizure diary chronicling 1203 seizures over 1079 days); two outpatients self-reported seizure frequencies. The extended diary revealed an inverse correlation between acetazolamide and proportion of seizures/day: 6%, 2% (days 1, 2 ON); 3%, 13%, 31%, 45% (days 1, 2, 3, 4 OFF). This patient later developed focal status epilepticus upon wean of antiseizure medications during a seropositive AE relapse that was remarkably aborted with acetazolamide monotherapy. The other three EMU patients averaged .56 seizures/day ON, and 3.81 seizures/day OFF (p = .004). The two outpatients reported seizure reductions from 3-5/day to 2/week, and 15-20/day to none, respectively, after initiation of cycling acetazolamide. Likely related to cerebral CO2/pH sensitivity, acetazolamide can be unusually effective in controlling pilomotor seizures in AE, chronically or in acute settings.

Utilization of APE2 and RITE2 scores in autoimmune encephalitis patients with seizures.

PURPOSE: Immune-mediated seizures are rare but are increasingly recognized as an etiology of seizures resistant to anti-seizure medications (ASMs). Antibody Prevalence in Epilepsy 2 (APE2) and Response to Immunotherapy in Epilepsy 2 (RITE2) scores were developed recently to identify patients who may be seropositive for serum central nervous system (CNS) specific antibodies (Ab) and may benefit from immunotherapy (Dubey et al. 2018). The goal of this study was to apply APE2 and RITE2 scores to an independent cohort of patients with seizures secondary to autoimmune encephalitis (AE) and to further verify the sensitivity and specificity of the scores. PRINCIPAL RESULTS: We conducted a retrospective study at Stanford University Hospital between 2008 and 2021 and included patients who had acute seizures and AE using diagnostic criteria from Graus (n = 34 definite AE, 10 probable AE, and 12 possible AE) (Graus et al. 2016). Patients were excluded if they did not have a serum Ab panel investigated or had alternate diagnoses (n = 55). APE2 and RITE2 scores were calculated based on clinical and diagnostic data (n = 56). Serum Ab were positive in 73 % of patients, in which 63 % cases carried CNS specific Ab. An APE2 score ≥ 4 had a sensitivity of 97 % and specificity of 14 % to predict a positive serum CNS specific Ab. A RITE2 score ≥ 7 had a sensitivity of 93 % and specificity of 60 % to predict seizure responsiveness to immunotherapy. CONCLUSION: APE2 and RITE2 scores had high sensitivities but low specificities to predict seropositivity and seizure responsiveness to immunotherapy in patients with autoimmune encephalitis with seizures.

Autoimmune and paraneoplastic seizures.

Seizures are a common feature of autoimmune encephalitis and are especially prevalent in patients with the commonest autoantibodies, against LGI1, CASPR2 and the NMDA, GABAB, and GABAA receptors. In this chapter, we discuss the classification, clinical, investigation, and treatment aspects of patients with these, and other autoantibody-mediated and -associated, illnesses. We highlight distinctive and common seizure semiologies which, often alongside other features we outline, can help the clinical diagnosis of an autoantibody-associated syndrome. Next, we classify these syndromes by either focusing on whether they represent underlying causative autoantibodies or T-cell-mediated syndromes and on the distinction between acute symptomatic seizures and a more enduring tendency to autoimmune-associated epilepsy, a practical and valuable distinction for both patients and clinicians which relates to the pathogenesis. We emphasize the more effective immunotherapy response in patients with causative autoantibodies, and discuss the emerging evidence for various first-, second-, and third-line immunotherapies. Finally, we highlight available clinical rating scales which can guide autoantibody testing and immunotherapy in patients with seizures of unknown etiology. Throughout, we relate the clinical and therapeutic observations to the immunobiology and neuroscience which drive these seizures.

High-Titer Anti-ZSCAN1 Antibodies in a Toddler Clinically Diagnosed with Apparent Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation Syndrome.

Severe obesity in young children prompts for a differential diagnosis that includes syndromic conditions. Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) syndrome is a potentially fatal disorder characterized by rapid-onset obesity associated with hypoventilation, neural crest tumors, and endocrine and behavioral abnormalities. The etiology of ROHHAD syndrome remains to be established, but recent research has been focusing on autoimmunity. We report on a 2-year-old girl with rapid-onset obesity during the first year of life who progressed to hypoventilation and encephalitis in less than four months since the start of accelerated weight gain. The patient had a high titer of anti-ZSCAN1 antibodies (348; reference range < 40), and the increased values did not decline after acute phase treatment. Other encephalitis-related antibodies, such as the anti-NDMA antibody, were not detected. The rapid progression from obesity onset to central hypoventilation with encephalitis warns about the severe consequences of early-onset ROHHAD syndrome. These data indicate that serial measurements of anti-ZSCAN1 antibodies might be useful for the diagnosis and estimation of disease severity. Further research is needed to determine whether it can predict the clinical course of ROHHAD syndrome and whether there is any difference in antibody production between patients with and without tumors.

Time to FIRE NORSE: A single acronym for a heterogeneous presentation. Further information from a case series and discussion of the literature.

PURPOSE: New-Onset Refractory Status Epilepticus (NORSE) is a rare and severe form of refractory status epilepticus without an apparent underlying cause at presentation or prior history of epilepsy. We aimed to describe the clinical features, etiology, treatment, and outcomes of NORSE in adults in a quaternary-level hospital in Saudi Arabia. METHODOLOGY: In this retrospective cohort study, inclusion criteria involved patients over 14 years old who met the 2018 consensus definition for NORSE. Patients were identified using a combination of medical record admission labels 'status epilepticus' and 'encephalitis', and continuous EEG reports documenting status epilepticus. Demographic, clinical, and radiological data were collected and then analyzed for factors correlated with specific etiologies, better functional outcomes, and future diagnosis of epilepsy. RESULTS: We found 24 patients presenting with NORSE between 2010 and 2021. Fever/infectious symptoms were the most common prodrome. Elevated inflammatory serum and cerebrospinal fluid markers in most patients. Brain MRI revealed T2/FLAIR hyperintensity patterns, predominantly affecting limbic and perisylvian structures. The etiology of NORSE varied, with immune-related causes being the most common. Long-term outcomes were poor, with a high mortality rate and most survivors developing drug-resistant epilepsy. CONCLUSION: This study provides valuable insights into NORSE's clinical characteristics, highlighting the heterogeneity of this condition. The poor outcome is likely related to the progressive nature of the underlying disease, where refractory seizures are a clinical symptom. Thus, we propose to focus future research on the etiology rather than the NORSE acronym.

Thymoma-associated autoimmune encephalitis with myasthenia gravis: Case series and literature review.

OBJECTIVES: This comprehensive review aimed to compile cases of patients with thymoma diagnosed with both autoimmune encephalitis (AE) and myasthenia gravis (MG), and describe their clinical characteristics. METHODS: Clinical records of 3 AE patients in the first affiliated hospital of Sun Yat-sen University were reviewed. All of them were diagnosed with AE between 1 November 2021 and 1 March 2022, and clinical evidence about thymoma and MG was found. All published case reports were searched for comprehensive literature from January 1990 to June 2022. RESULTS: A total of 18 cases diagnosed with thymoma-associated autoimmune encephalitis (TAAE) and thymoma-associated myasthenia gravis (TAMG) were included in this complication, wherein 3 cases were in the first affiliated hospital of Sun Yat-sen University and the other 15 were published case reports. 5/18 patients had alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antibody (AMPAR-Ab) in their serum and cerebrospinal fluid (CSF). All of them had positive anti-acetylcholine receptor antibody (AChR-Ab). And 12/18 patients showed a positive response to thymectomy and immunotherapy. Besides, thymoma recurrences were detected because of AE onset. And the shortest interval between operation and AE onset was 2 years in patients with thymoma recurrence. CONCLUSIONS: There was no significant difference in the clinical manifestations between these patients and others with only TAMG or TAAE. TAAE was commonly associated with AMPAR2-Ab. Significantly, AE more commonly heralded thymoma recurrences than MG onset. And the intervals of thymectomy and MG or AE onset had different meanings for thymoma recurrence and prognoses of patients.

Sudden unexpected death in epilepsy and ictal asystole in patients with autoimmune encephalitis: a systematic review.

OBJECTIVE: As autoimmune encephalitis (AE) often involves the mesial temporal structures which are known to be involved in both sudden unexpected death in epilepsy (SUDEP) and ictal asystole (IA), it may represent a good model to study the physiopathology of these phenomena. Herein, we systematically reviewed the occurrence of SUDEP and IA in AE. METHODS: We searched 4 databases (MEDLINE, Scopus, Embase, and Web of Science) for studies published between database inception and December 20, 2022, according to the PRISMA guidelines. We selected articles reporting cases of definite/probable/possible/near-SUDEP or IA in patients with possible/definite AE, or with histopathological signs of AE. RESULTS: Of 230 records assessed, we included 11 cases: 7 SUDEP/near-SUDEP and 4 IA. All patients with IA were female. The median age at AE onset was 30 years (range: 15-65), and the median delay between AE onset and SUDEP was 11 months; 0.9 months for IA. All the patients presented new-onset seizures, and 10/11 also manifested psychiatric, cognitive, or amnesic disorders. In patients with SUDEP, 2/7 were antibody-positive (1 anti-LGI1, 1 anti-GABABR); all IA cases were antibody-positive (3 anti-NMDAR, 1 anti-GAD65). Six patients received steroid bolus, 3 intravenous immunoglobulin, and 3 plasmapheresis. A pacemaker was implanted in 3 patients with IA. The 6 survivors improved after treatment. DISCUSSION: SUDEP and IA can be linked to AE, suggesting a role of the limbic system in their pathogenesis. IA tends to manifest in female patients with temporal lobe seizures early in AE, highlighting the importance of early diagnosis and treatment.

Incident anti-LGI1 autoimmune encephalitis during dementia with Lewy bodies: when Occam razor is a double-edged sword.

In Dementia with Lewy bodies (DLB), rapid cognitive decline and seizures seldom complicate the typical clinical course. Nevertheless, concurrent, treatable conditions may be responsible. We report a case of DLB with superimposed anti-LGI1 encephalitis, emphasizing the importance of thorough diagnostic reasoning beyond the simplest explanation amid distinct clinical cues.

[A case of Alice in Wonderland syndrome after Epstein-Barr virus (EBV) encephalitis: a mimicry of focal epileptic seizure].

A 30-year-old man who received infliximab for treatment of Crohn's disease developed Epstein-Barr virus (EBV) encephalitis, which responded well to therapy; however, he had left lower visual field loss following treatment. The patient noticed peculiar symptoms 9 months after recovery from encephalitis; objects in his view appeared smaller or larger than their actual size (micropsia/macropsia). Moreover, it appeared that objects outside moved faster or slower than their actual speed of movements and moving objects appeared as a series of many consecutive snap shots. His vision was blurred, and he had visual difficulties and a sensation that his body was floating. These symptoms mainly appeared following fatigue and persisted over approximately 10 years. Based on cerebrospinal fluid analysis, brain MRI, N-isopropyl-p-123I-iodoamphetamine with single photon emission computed tomography, fluorodeoxyglucose positron emission tomography, and electroencephalography, we excluded both recurrent encephalitis and focal epileptic seizures. By taking all symptoms and other evaluation findings into account, the patient most likely suffered from "Alice in Wonderland syndrome" which is primarily associated with cortical dysfunction in the right temporo-parieto-occipital area as the consequence of previous acute EBV encephalitis.

The relationship between HIV-1 neuroinflammation, neurocognitive impairment and encephalitis pathology: A systematic review of studies investigating post-mortem brain tissue.

The activities of HIV-1 in the central nervous system (CNS) are responsible for a dysregulated neuroinflammatory response and the subsequent development of HIV-associated neurocognitive disorders (HAND). The use of post-mortem human brain tissue is pivotal for studying the neuroimmune mechanisms of CNS HIV infection. To date, numerous studies have investigated HIV-1-induced neuroinflammation in post-mortem brain tissue. However, from the commonly investigated studies in this line of research, it is not clear which neuroinflammatory markers are consistently associated with HIV neurocognitive impairment (NCI) and neuropathology (i.e., HIV-encephalitis, HIVE). Therefore, we conducted a systematic review of the association between neuroinflammation and NCI/HIVE from studies investigating post-mortem brain tissue. Our aim was to synthesise the published data to date to provide commentary on the most noteworthy markers that are associated with NCI/HIVE. PubMed, Scopus, and Web of Science databases were searched using a search protocol designed specifically for this study. Sixty-one studies were included that investigated the levels of inflammatory markers based on their gene and protein expression in association with NCI/HIVE. The findings revealed that the (1) transcript expressions of IL-1ß and TNF-α were consistently associated with NCI/HIVE, whereas CCL2 and IL-6 were commonly not associated with NCI/HIVE, (2) protein expressions of CD14, CD16, CD68, Iba-1, IL-1ß and TNF-α were consistently associated with NCI/HIVE, while CD45, GFAP, HLA-DR, IL-1 and IL-6 were commonly not associated with NCI/HIVE, and (3) gene and protein expressions of CNS IL-1ß and TNF-α were consistently associated with NCI/HIVE, while IL-6 was consistently not associated with NCI/HIVE. These markers highlight the commonly investigated markers in this line of research and elucidates the neuroinflammatory mechanisms in the HIV-1 brain that are involved in the pathophysiology of NCI/HIVE. These markers and related pathways should be investigated for the development of improved diagnostics, prognostics, and therapeutics of HAND.